The majority of lung cancers are lung adenocarcinomas (LAC) that occur peripherally in the lung. When detected at an earlier stage (Stage II-III), these patients undergo curative-intent surgical resection along with pre- or post-operative chemotherapy. Nearly half of these patients recur within 5 years. Currently, beyond clinical stage, there are no radiological or molecular biomarkers exist to further inform clinical decision making in LAC patient management. In order to improve prognostication, we have studied 600 LAC tumors and identified mesothelin, a cancer cell-surface antigen, as an indicator of worse prognosis. LAC overexpressing mesothelin are associated with factors known to promote tumor aggressiveness and chemotherapy resistance.

To target this subset of LAC tumors that are therapy-resistant, we have developed mesothelin-targeted immunotherapy. Utilizing mesothelin-specific chimeric antigen receptors, we can transduce T cells, human primary immune cells that target mesothelin-expressing LAC. We have successfully tested the efficacy of mesothelin-targeted T cells in orthotopic LAC mouse models. The strategies we wish to pursue via this proposal aim to increase recognition of tumor antigens, enhance anti-tumoral functions, and sustain T cell persistence and function in LAC patients. Furthermore, our research strategy in this application reflects well thought out integration of immunotherapy into current standard of care of LAC cisplatin-based chemotherapy.

This adoptive T-cell therapy approach is predicated on recent successes in melanoma. The occurrence of some remarkable albeit infrequent complete responses in patients with metastatic disease not only underscores the potential of targeted T cells, but also the need to increase the potency of these therapies through improvements in the host conditioning. In order to facilitate effective clinical translation, we propose to investigate the beneficial effect of combining targeted T-cell therapy with existing chemotherapy with solid scientific reason. Although T cells may be targeted to disease site, their survival and function are dependent on co-stimulation, and such co-stimulatory molecules may not reach the tumor in adequate concentration without causing systemic toxicity. We will deliver IL-12, a powerful cytokine already proven to be beneficial in LAC therapy, utilizing mesothelin-targeted IL-12 secreting T cells and thereby avoid potential toxicity reported with its systemic administration.

Our laboratory has pioneered adoptive T-cell therapies for leukemia and prostate cancer using genetically targeted T cells. Our Gene Transfer and Somatic Cell Engineering facility within the Center for Cell Engineering is well equipped and has developed a Food and Drug Administration-approved process to rapidly generate tumor-targeted T cells from peripheral blood T cells. We anticipate being in a position to initiate a Phase 1 clinical trial by the end of this award.